Synaptic function of BK channel-interacting proteins

阿尔茨海默病(AD)是一种神经退行性疾病，对许多人造成影响。大多数早发病例 家族性AD与早老素基因突变有关。以前对早老素的研究主要集中在它们在脑内的作用。 淀粉样蛋白β(Aβ)的产生是因为Aβ斑块在脑组织中的积聚通常被认为是 阿尔茨海默病的主要原因。然而，淀粉样蛋白假说受到质疑，因为所有的抗淀粉样蛋白临床试验 都失败了。因此，有必要探讨早老素在AD中的其他潜在作用机制。其中 已知的早老素突变的影响是神经递质释放减少和钙稳态失调， 这两种机制都是AD的潜在机制。众所周知，早老素的突变会导致减数 神经递质释放和钙代谢紊乱，与其相关并可能由其引起 Ryanodine受体表达降低。然而，尚不清楚早老素是如何调节兰尼定受体的。 这项提议是为了验证早老素通过作用于 其他一些调节蛋白。线虫秀丽线虫作为动物模型被用来识别 这些假定的调节蛋白是因为哺乳动物系统中的许多细胞机制，包括 早老素在突触和兰尼定受体中的功能，在蠕虫中是保守的。这样做的具体目的是 建议如下：1)通过质量鉴定兰尼定受体表达的可能调控蛋白 光谱和rna-seq，以及2)确定识别的蛋白质是否对早老素的作用是必需的。 神经递质释放和兰尼定受体表达。我们的长期目标是说明是否和 神经递质释放减少和兰尼定受体功能在AD发病机制中的作用 由早老素突变引起。

Alzheimer’s disease (AD) is a neurodegenerative disorder inflicting many people. Most cases of early-onset familial AD are linked to mutations of presenilins. Previous studies on presenilins have focused on their roles in the generation of amyloid β (Aβ) because accumulation of Aβ plaques in brain tissue is generally considered the primary cause of AD. However, the amyloid hypothesis is being questioned because all anti-amyloid clinical trials have failed. Therefore, it is necessary to explore other potential mechanisms of presenilin function in AD. Among the known effects of presenilin mutations are reduced neurotransmitter release and calcium dyshomeostasis, which are both putative underlying mechanisms of AD. It is known that mutations of presenilins cause reduced neurotransmitter release and calcium dyshomeostasis, which are associated with and potentially caused by decreased ryanodine receptor expression. However, it is unknown how presenilins regulate ryanodine receptors. This proposal is to test the hypothesis that presenilins regulate ryanodine receptor expression by acting through some other regulatory proteins. The nematode Caenorhabditis elegans is used as an animal model to identify the putative regulatory proteins because many cellular mechanisms in mammalian systems, including the roles of presenilins in synaptic and ryanodine receptor function, are conserved in worms. The specific aims of this proposal are: 1) identify candidates for the putative regulatory proteins of ryanodine receptor expression by mass spectrometry and RNA-seq, and 2) determine whether the identified proteins are required for presenilins’ roles in neurotransmitter release and ryanodine receptor expression. Our long-term goal is to illustrate whether and how reduced neurotransmitter release and ryanodine receptor function play a role in the pathogenesis of AD caused by presenilin mutations.